The invention relates to a device for carrying out in-vivo measurements of quantities in living organisms, comprising a catheter-like tube that accommodates, in a removable manner, a needle that is provided for inserting the tube in the organism; at least one opening in the wall of the tube; and a sensor for detecting the quantity to be measured in the interior of the tube.
It is frequently necessary in many areas in the field of medicine and in comparable fields to measure in a repeated or continuous manner concentrations or compositions of body fluids primarily for the purpose of being able to detect disorders of the homeostasis and to be able to treat such disorders, if necessary. For example, diabetes mellitus is a disorder of the metabolism that is reflected by various symptoms, whereby it is possible to control the concentration of the blood glucose by a therapy with insulin. Although this therapy with insulin substantially promotes the well-being of the patient, it is not possible to prevent late complications such as, for example premature blindness, heart and kidney failure, or neuropathies in most cases, but only to delay such complications. One of the most important causes for the late consequences of this disease is the not optimal coordination of the insulin injections with the blood glucose. Therefore, so as to be able to adapt the insulin injections to the needs of the body as required, the glucose concentration has to be measured repeatedly (or continuously) in a precise manner.
All kinds of different methods have been proposed for measuring the glucose in the organism, including blood sugar-measuring devices; non-invasive measuring methods; indirect determination of the glucose via other body parameters; or measurement of the glucose in body fluids other than the blood, for example in the sputum, in the perspiration, or in the urine. Because of the problems encountered when measurements are taken in such fluids, quantification of the glucose in the fluid of the tissue, which is closely connected with the plasma glucose, has been increasingly given more attention in the last few years. Problems arising in the blood such as, for example coagulation, the risk of infection, or protein loading, are highly reduced in this connection if they cannot be avoided, to begin with.
Various possibilities for measuring the glucose in the fluid of the tissue in a continuously manner have been proposed as well:
(1) Minimally invasive sampling methods such as the open micro-perfusion technique, the micro-dialysis, or the ultra-filtration technique.
(2) Sensors that are directly inserted in the tissue; or
(3) Techniques by which the tissue fluid is collected through the skin (the so-called suction technique, inverse iontophoresis).
In addition to the open micro-perfusion method and micro-dialysis, sensors that are directly inserted in the tissue have been found to be particularly well-suited for a continuous measuring system.
In connection with the open micro-perfusion technique and micro-dialysis, perfusion of a catheter inserted in the tissue is carried out with a rinsing liquid that, in connection with the open micro-perfusion method, mixes with the fluid of the tissue, whereas in connection with micro-dialysis, an exchange takes place via a membrane. This membrane, on the one hand, permits that the exchange of molecules between the tissue fluid and the rinsing liquid can be controlled in a selective manner; on the other hand, this property is altered by the deposits of endogenous substances (predominantly of proteins, but also of cells). Such deposits go hand in hand with a change in the transport properties of the molecules via the membrane, which is reflected by a diminished concentration of the molecules in the rinsing liquid. This drawback can be circumvented by macroscopic perforations in connection with the open micro-perfusion technique.
The equilibration between the fluid of the tissue and the rinsing liquid is a function of the exchange area and the flow rate of the rinsing liquid. If the flow rate is infinite, complete equilibration between the two liquids takes place. Because of the low flow rate, two decisive drawbacks ensue for the measurement of the substances in the rinsing liquid: firstly, the amount of fluid collected per unit of time is very small, and secondly, the delay caused by the length of the hose (system delay) will increase accordingly.
A higher flow rate is frequently selected for that reason in order to make more liquid available more rapidly. The drawback of this mode of operation consists in the not-complete mixing of the two liquids, which, if possible, has to be compensated by measuring other parameters. This causes additional requirements that the measuring technique needs to satisfy, which is found to be difficult particularly in connection with on-line measurements.
In addition to the sampling methods, which permit an ex-vivo measurement (sensor is located outside of the body), proposals already exist for in-vivo measurements, whereby the sensor is directly inserted in the tissue. In addition to the higher requirements the sensor needs to meet with respect to bio-compatibility, mechanical stability and size, it is necessary to pay attention to the problem posed by the calibration of the sensor. Although the sensors exhibit very good in-vivo characteristics, characteristics are observed that are changed in vivo. In order to take such changes into account, different starting points exist: a frequently employed starting point is the calibration of the sensor value against one or more blood values, whereby it is implicated that, in the case of a glucose measurement, the concentration of the glucose in the fluid of the tissue is equal to the concentration in the blood. So as to be able to render this a correct statement, the concentration of the glucose has to be in a state of equilibrium between the blood and the fluid of the tissue because a shift in terms of time exists between these two compartments. In addition to the painful stress affecting the person involved, calibrating changes xe2x80x9cawayxe2x80x9d (for example infections in the tissue, encapsulation of the sensor) constitutes a substantial shortcoming of this measurement.
So as to avoid the drawbacks of the sampling methods (time delay), incomplete equilibration, a membrane disposed in between) and the implanted sensor (no calibration possibility, mechanical stability), a sensor (e.g. a glucose, lactate or glutamate sensor) can be inserted in a specially shaped catheter or general a tube or hose, and inserted in the tissue with the help of such a catheter or tube or hose); compare, for example U.S. Pat. No. 5,299,571 A, or U.S. Pat. No. 5,568,806 A. The catheter has a macroscopic opening, so that an exchange can take place between the fluid of the tissue and the sensor. After the sensor has been inserted in the respective tissue with the help of a setting needle present in a lumen, said setting needle is removed from the catheter. The setting needle or the associated lumen take up a mayor portion of the cross section of the catheter, and the sensor is arranged in a fixed manner in the lumen located adjacent to the lumen receiving the setting needle. The aforementioned opening in the catheter tube is located adjacent to the sensor. Suitable conduits lead from said sensor to the outside in order to permit a connection to an electronic measuring system. The manufacture of the catheter tube requires relatively much expenditure because of the two special lumens, whereby, furthermore, a relatively large cross section, notably the one receiving the setting needle, cannot be used for carrying out the measurement and has to be viewed as a lost volume.
Other types of catheter systems have already been proposedxe2x80x94compare, for example U.S. Pat. No. 5,779,665 A; U.S. Pat. No. 5,586,553 A; or U.S. Pat. No. 5,390,671 A, whereby the setting needle is present there outside of the catheter tube, approximately parallel with said catheter tube (U.S. Pat. No. 5,779,665 A), or with inclusion of the catheter tube. This entails drawbacks when the catheter is set such as, for example the impermissible fact that the catheter tube is being taken along via a thread (U.S. Pat. No. 5,779,665 A1), or causes pain when the relatively thick unit comprising the setting needle and the catheter tube is inserted. In connection with such known arrangements, the sensor is present in the remaining catheter tube, whereby it has been proposed also (compare U.S. Pat. No. 5,390,671 A) to mount the sensor in a displaceable manner in a rigid, strip-shaped carrier in the catheter tube, said carrier being bent at a right angle.
In connection with the last-mentioned embodiments, a set of setting utensils is provided or required for setting the catheter with the sensor in place. This entails additional expenditure.
Now, the problem of the invention is to provide a measuring system of the type specified above that permits working with the smallest of cross sections when the catether-like protective tube is set in place, so that the catheter or the catheter-like tube can be set in a simple manner and largely without causing pain, whereby, furthermore, no set of setting utensils and no trained personnel are needed, but self-application is made possible instead.
The device as defined by the invention of the type specified above is characterized in that the sensor mounted on a separate, oblong carrier as it is known per se, the cross sectional dimensions of which are smaller than the ones of the interior of the tube, and can be inserted in said tube after the setting needle has been pulled out of the tube.
In connection with the present device, therefore, the lumen of the catheter-like protective tube is used in two ways, so that no second lumen is required (for the sensor). In the preferably only one lumen of the tube, the setting needle is accommodated first by inserting it in the tissue with the help of the tube. The setting needle is subsequently pulled back, which releases the lumen of the tube, in order to then insert the sensor with the help of a carrier. The carrier, of course, has to possess a certain rigidity in order to permit such insertion in the catheter-like tube, even though a certain flexibility of the carrier is entirely possible and advantageous as well. This technique permits a minimal cross section of the tube with the sensor finally accommodated therein, and it is possible also to directly measure the respective quantity such as, for example glucose etc. After the tube has been set in place, it is possible also in this connection to replace the sensor without requiring another piercing, i.e. setting of the catheter.
Furthermore, owing to the fact that the sensor carrier has smaller cross sectional dimensions than the lumen of the tube, a space is created between the catheter tube and the carrier or sensor, through which liquids can be introduced from the outside. Preferably, provision is made in this connection that a channel having a generally ring-shaped cross section for a rinsing or calibration liquid or the like is formed between the sensor carrier in the installed condition, and the inner wall of the tube.
The admitted liquids per se may assume different functions as follows:
(1) The liquid contains the substance to be measured and may therefore serve as the calibration medium (e.g. Ringer solution with 5 mmols/liter addition of glucose for calibrating glucose sensors;
(2) due to an increased high speed of the liquid, it is possible to remove deposits on the sensor, i.e. to flush such deposits away;
(3) it is possible to add substances to the liquid in order to cause different effects such as, for example buffers for a constant pH, high-oxygen agents against an oxygen deficit in the tissue, infection-inhibiting agents, increase of the permeability, or substances lowering the blood sugar (e.g. insulin).
Of primary importance in this connection is thexe2x80x94periodicxe2x80x94calibration of the measuring device with the help of a channel formed in the passage between the sensor carrier and the wall of the tube, and likewise the periodic rinsing, which is useful for obtaining an exact measurement.
However, it is particularly advantageous if the separate sensor carrier has the shape of the tube because if the carrier of the sensor is realized in the form of a tube (and the sensor is positioned on the outer side of the tube), it is possiblexe2x80x94due to the inner lumen of the carrier tubexe2x80x94to additionally introduce in an advantageous manner a medication, for example insulin, if such a substance may not come into any direct contact with the sensor.
For an increased feed of said substance or substances, it is advantageous also in the present case if the tubular sensor carrier has at least one opening in its wall that is positioned adjacent to its open distal end.
In order to prevent the substance from flowing back into the space between the sensor carrier and the catheter tube and to thereby safely avoid any direct contact of the substance with the sensor, it is favorable, furthermore, if a ring seal providing sealing against the inner wall of the catheter-like tube is arranged on the tubular carrier in a site located between the open distal end or, if need be, the opening in the wall of the tubular sensor carrier, on the one hand, and the sensor on the other. Therefore, if a seal is thus mounted between the tip of the carrier and the sensor, the substance can exit only into the tissue.
Therefore, it is overall possible with the embodiment of the device as defined by the invention to measure directly on site, and the sensor can be calibrated and xe2x80x9cmaintainedxe2x80x9d. Furthermore, active substances can be introduced for the measurement, and it is possible also to feed substances into the tissue in response to the measuring result by penetrating the tissue only once.
When the sensor is directly inserted in the tissue, the ambient temperature is preset by the body temperature, which is relatively constant. Therefore, a measurement of the temperature as it is required in connection with ex-vivo measurements, can be omitted. By omitting the pumping devices, which are required in connection with sampling methods for ex-vivo measurements, the structure of the device is substantially simplified, which reduces the costs. Hose pumps are employed, as a rule, in connection with sampling methods because different directions of flow can be synchronized with such pumps, whereby most of the energy is consumed with such type of pumps for deforming the pump hoses, so that the consequence is a very poor degree of efficiency (which is critical in particular in conjunction with portable devices). Since it is possible in connection with the device as defined by the invention to employ injector pumps for feeding calibrating or rinsing liquid, or active and therapeutic substances, the operation of the system, furthermore, requires less energy.
Moreover, by omitting suction pumps, no dilution of the tissue fluid by a rinsing or calibrating solution liquid will occur with the device as defined by the invention in normal measuring operations, which means that a completely equilibrated solution is available on the sensor. This also means, furthermore, that it is no longer necessary to determine the re-finding rate. Since no tissue fluid is extracted from the body permanently, the tissue fluid cannot become poor around the catheter. The only consumption of tissue fluid takes place directly on the sensor; however, such consumption is negligible.
For the intensive, safe contact of the sensor with the tissue fluid, it is also advantageous in this connection if the wall of the catheter-like tube has several openings successively located one after the other in the axial direction within the area of the sensor. In this way, tissue fluid can flow to the sensor through a number of openings, i.e. macroscopic perforations in the wall of the catheter tube, which, furthermore, means that the given position of the sensor is relatively uncritical, so that when the carrier with the sensor is pushed into the catheter-like tube, no exact positioning of the sensor has to be achieved after the setting needle has been pulled back.
In order to safely avoid any damage to the sensor by rubbing on the inner wall of the catheter-like tube when the carrier with the sensor is pushed into the catheter-like tube, the aim should be that the sensor has the smallest possible dimensions in the radial direction, i.e. the sensor should project from the carrier as little as possible. Accordingly, it is advantageous if the sensor is produced by application of the thin-film technology or silicon technology, as it is known per se. Furthermore, it is favorable for this purpose as well if the sensor is at least partially embedded in the carrier. In this connection, the sensor may have an expanse in the longitudinal direction of the carrier that is greater than it is usually the case, which is particularly advantageous if the catheter-like tube has a plurality of apertures.
The measuring principle of the sensor is known per se and may consist of physical and chemical methods as well as also combinations of the two methods. For example, an electrochemical measurement is suitable for the determination of the substance. According to current practice, an amperometric method with constant polarization voltage for the quantification is particularly well-suited in this connection (see U.S. Pat. No. 5,462,645 A). In this process, an enzyme (e.g. glucose oxidase, glutamate oxidase, lactate oxidase, etc.) is converted according to a chemical reaction into hydrogen peroxide, which is oxidized on an electrode by the constant polarizing voltage. The quantity of the sensor current generated in this process is dependent upon the concentration of the substance to be determined. The following applies by way of example to glucose measurements:       Glucose    +                            O          2                ⁢                  ⟶          Glucoseoxidase                ⁢        Gluconic            ⁢              xe2x80x83            ⁢      Acid        +                  H        2            ⁢              O        2                                H        2            ⁢                        O          2                ⁢                  ⟶                                    +              600                        ⁢                          xe2x80x83                        ⁢            mmV                          ⁢                  O          2                      +          2      ⁢              H        +              +          2      ⁢              e        -            
Various technologies are available for the manufacture of the sensors (see, for example FRASER, D.: Biosensors In The Body. Wiley 1997, page 199f). A technique commonly employed at the present time would be also the thick-film technology, by which is it possible to realize structures of 0.1 mm. However, with the thin-film technology, it is possible to obtain structures in the xcexcm-range, and with the silicon-technology it is possible to build sensors even in the sub-xcexcm range. Since the invasiveness of the system increases with the increase in the diameter, it is important that the sensor has small dimensions in the radial direction. Especially the thin-film technology or the silicon technology are well-suited for that reason for realizing the sensor. So that the volume required for the sensor can nonetheless be made available, the sensor can be expanded in the axial direction, as mentioned before. A sensor comprising a size and technology that could be considered for realizing the present measuring system is represented by the sensor described by JOBST G ET AL in: Thin-Film Microbiosensors For Glucose-Lactate Monitoring, Anal. Chem. (68) 18, pp 3173-3179, 1996.
An embodiment of the catheter that is feasible within the framework of the invention, comprises perforating (by means of a laser beam or using a mechanical drill) a commercially available vein-dwelling cannula. Various sizes of the catheter are possible, whereby the outside diameter may be in the range of from 0.6 mm to 2.0 mm. The diameter of the carrier for the sensor can be adapted to the inner tube, so that the sensor mounted on the surface of the carrier can be inserted in the catheter without any problems. With the smallest embodiment of the arrangement (outside diameter of the catheter=0.6 mm; diameter of the carrier=0.3 mm), which conforms to the size of the needle of an insulin pump, the radial expanse of the sensor may amount to 0.15 mm at the most. These dimensions can be realized without any problem with the aforementioned technologies, primarily with the thin-film and the silicon technologies.
Finally, for safety reasons, i.e. in order to safely exclude any damage to the connection cables and to the sensor as well, it is advantageous, furthermore, if the sensor is connected to electrical cables that are embedded in the carrier.